Production process and intermediate of tetrazole compound

ABSTRACT

There are disclosed an industrially favorable process for producing a tetrazole compound of general formula (1): ##STR1## characterized in that a nitrile of general formula (2): 
     
         R.sup.1 CN                                                 (2) 
    
     is reacted with hydrazine or a salt thereof in the presence of a catalyst, followed by reaction with a nitrous acid compound of general formula (3): 
     
         ANO.sub.2                                                  (3) 
    
     or a nitrile of general formula (2) is reacted with hydrogen sulfide, followed by reaction with an alkyl halide of general formula (4): 
     
         R.sup.4 J                                                  (4) 
    
     with hydrazine or a salt thereof, and then with a nitrous acid compound of general formula (3); and an intermediate of general formula (5): 
     
         R.sup.1 C(=R.sup.5)R.sup.6                                 (5) 
    
     which is useful for the production of the tetrazole compound (in which R 1  to R 6 , A and J in the above formulas are as defined in the specification).

INDUSTRIAL FIELD FOR UTILIZATION

The present invention relates to production processes and intermediatesof tetrazole compounds. More particularly, it relates to2-(tetrazol-5-yl)-4-oxo-4H-benzopyran derivatives which are known to bepharmacologically useful from the viewpoint of their antagonistic actionto leukotrienes such as leukotrienes C and D, and it also relates to2-(tetrazol-5-yl)-1,1'-biphenyl derivatives which are known to bepharmacologically useful from the viewpoint of their antagonistic actionto angiotensin II. Further, it relates to processes for producing5-phenyltetrazole derivatives which are useful as intermediates of thebiphenyl derivatives, and it also relates to intermediates which areuseful in their production.

Prior Art

As the process for producing tetrazole compounds such as2-(tetrazol-5-yl)-4-oxo-4H-benzopyran derivatives,2-(tetrazol-5-yl)-1,1'-biphenyl derivative and 5-phenyltetrazolederivatives, there has been known a process with an azide such as sodiumazide, trialkyl tin azide or trimethylsilyl azide.

However, since azides are reacted with water or acids to producehydrogen azide having toxic and explosive properties, the concentrationof hydrogen azide in the gas phase in the upper part of a reactor shouldbe strictly controlled during the reaction. It has been known thatazides are liable to form an explosive salt with heavy metals.Therefore, the application of such a process with an azide on anindustrial scale is disadvantageous from the viewpoint of its safety.Further, tin reagents such as trialkyl tin azide have drawbacks thatthey require a complicated procedure for the isolation of a productbecause of its lipophilicity and that tin-containing waste matters areformed in large quantities.

As the process for producing 2-(tetrazol-5-yl)-1,1'-biphenyl derivativesor 5-phenyltetrazole derivatives, another process is described in J.Org. Chem., 1991, 56, pp. 2395-2400, in which process biphenylcarboxylicacids or phenylcarboxylic acids are converted into their amides withcyanoethylamine, followed by chlorination with phos- phorouspentachloride, and reaction with hydrazine and then with dinitrogentetroxide gas.

This process, however, has disadvantages that the yield of a desiredproduct is not satisfactory, that the step of deprotecting a cyanoethylgroup used as a protecting group is needed, and that the production onan industrial scale finds difficulty in using phosphorous pentachloride.

Objects of the Invention

It is an object of the present invention to provide a process forproducing tetrazole compounds with safety in an industrially favorablemanner.

It is another object of the present invention to provide intermediatesuseful for the production of the tetrazole compounds.

These and other objects and excellent advantages will be understood fromthe following description.

SUMMARY OF THE INVENTION

The present inventors have intensively studied on a process forproducing tetrazole compounds. As a result, they have found that theabove problems can be solved and the desired products can be obtainedwith safety in an industrially favorable manner by a process throughamidrazone compounds with nitrile compounds as the starting materials,and they have made further studies, thereby completing the presentinvention.

Thus, the present invention provides:

1! a process for producing a tetrazole compound of general formula (1):##STR2##

wherein R¹ is as defined below, characterized in that a nitrile ofgeneral formula (2):

    R.sup.1 CN                                                 (2)

wherein R¹ is a 4-oxo-4H-benzopyranyl group optionally substituted withR² or a phenyl group optionally substituted with X, in which R² is ahydroxy group, a halogen atom, an R³ CONH group, a nitro group, a C₁ -C₅alkyl or C₁ -C₅ alkoxy group; R³ is a C₁ -C₂₀ alkyl group, a phenylgroup, a phenyl-substituted (C₁ -C₂₀) alkyl group, a phenyl-substituted(C₁ -C₂₀) alkoxyphenyl group or a (C₁ -C₂₀) alkoxyphenyl group; X is ahalogen atom, a phenyl group optionally substituted with Y, a C₁ -C₂₀alkyl group, a phenyl-substituted (C₁ -C₂₀) alkyl group, aphenyl-substituted (C₁ -C₂₀) alkoxy group or a C₁ -C₂₀ alkoxy group; andY is a C₁ -C₂₀ alkyl group, a C₁ -C₂₀ alkyl group substituted with oneor more hydroxy groups with at least one hydrogen atom in the hydroxygroup being optionally replaced for protection, a C₁ -C₂₀ alkyl groupsubstituted with one or more amino groups with at least one hydrogenatom in the amino group being optionally replaced for protection, a C₁-C₂₀ alkyl group with at least one hydrogen atom being replaced by ahalogen atom, a C₁ -C₂₀ alkoxy group, a C₁ -C₂₀ alkoxy group substitutedwith one or more hydroxy groups with at least one hydrogen atom in thehydroxy group being optionally replaced for protection, a C₁ -C₂₀ alkoxygroup substituted with one or more amino groups with at least onehydrogen atom in the amino group being optionally replaced forprotection, or a C₁ -C₂₀ alkoxy group with at least one hydrogen atombeing replaced by a halogen atom, is reacted with hydrazine or a saltthereof in the presence of a catalyst, followed by reaction with anitrous acid compound of general formula (3):

    ANO.sub.2                                                  ( 3)

wherein A is a hydrogen atom, an alkali metal, an alkaline earth metalor a C₁ -C₂₀ alkyl group;

2! a process for producing tetrazole compound (1), characterized in thatnitrile (2) is reacted with hydrogen sulfide, followed by reaction withan alkyl halide of general formula (4):

    R.sup.4 J                                                  (4)

wherein R⁴ is a C₁ -C₂₀ alkyl group and J is a halogen atom, withhydrazine or a salt thereof, and then with nitrous acid compound (3);and

3! an amide of general formula (5):

    R.sup.1 C(=R.sup.5)R.sup.6                                 ( 5)

wherein R¹ is as defined above; R⁵ is a sulfur atom or an NH group; andR⁶ is an NH₂ group, an SR⁴ group or an NHNH₂ group, in which when R⁵ isa sulfur atom, then R⁶ is an NH₂ group, and when R⁵ is an NH group, thenR⁶ is an SR⁴ group or an NHNH₂ group; and R⁴ is as defined above.

DETAILED DESCRIPTION OF THE INVENTION

As the R¹ in the nitrile (2) used in the present invention, there can bementioned 4-oxo-4H-benzopyranyl groups optionally substituted with R² orphenyl groups optionally substituted with X.

As the R², there can be mentioned hydroxy group; halogen atoms such asfluorine, chlorine, bromine and iodine atoms; R³ CONH groups; nitrogroup; straight chain or branched C₁ -C₅ alkyl groups such as methyl,ethyl, propyl, butyl and pentyl groups; and straight chain or branchedC₁ -C₅ alkoxy groups such as methoxy, ethoxy, propoxy, butoxy andpentoxy groups.

As the R³, there can be mentioned straight chain or branched C₁ -C₂₀,preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkyl groups such asmethyl, ethyl, propyl, butyl, pentyl, octyl, decyl, pentadecyl andoctadecyl groups; phenyl group; straight chain or branched C₁ -C₂₀,preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkyl groups with one ofthe hydrogen atoms being replaced by a phenyl group, such as benzyl,phenethyl, phenylpropyl, phenylbutyl, phenyloctyl, phenylpentadecyl and1-phenylethyl groups; straight chain or branched (C₁ -C₂₀, preferably C₁-C₁₀, and more preferably C₁ -C₅) alkoxyphenyl groups with one of thehydrogen atoms in the alkoxy group being replaced by a phenyl group,such as benzyloxyphenyl, phenethyloxyphenyl, phenylpropyloxyphenyl,4-phenylbutoxyphenyl, 3-phenylbutoxyphenyl, phenylpentadecyloxphenyl and1-phenylethoxyphenyl groups; and straight chain or branched (C₁ -C₂₀,preferably C₁ -C₁₀, and more preferably C₁ -C₅) alkoxyphenyl groups suchas methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl,octyloxyphenyl, pentadecyloxyphenyl, octadecyloxyphenyl,1,1-dimethylmethoxyphenyl and 1,1,1-trimethylmethoxyphenyl groups.

As the X, there can be mentioned halogen atoms; phenyl groups optionallysubstituted with Y; straight chain or branched C₁ -C₂₀, preferably C₁-C₁₀, and more preferably C₁ -C₅, alkyl groups such as methyl, ethyl,propyl, butyl, pentyl, octyl, decyl, pentadecyl and octadecyl groups;straight chain or branched C₁ -C₂₀, preferably C₁ -C₁₀, and morepreferably C₁ -C₅, alkyl groups with one of the hydrogen atoms beingreplaced by a phenyl group, such as benzyl, phenethyl, phenylpropyl,phenylbutyl, phenyloctyl, phenylpentadecyl and3-phenyl-2-methylpropionyl groups; straight chain or branched C₁ -C₂₀,preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkoxy groups with oneof the hydrogen atoms in the alkoxy group being replaced by a phenylgroup, such as benzyloxy, phenethyloxy, phenylpropyloxy, 4-phenylbutoxy,3-phenylbutoxy, phenylpentadecyloxy and 1-phenylethoxy groups; andstraight chain or branched C₁ -C₂₀, preferably C₁ -C₁₀, and morepreferably C₁ -C₅, alkoxy groups such as methoxy, ethoxy, propoxy,butoxy, pentoxy, octyloxy, decyloxy, pentadecyloxy and octadecyloxygroups.

As the Y, there can be mentioned straight chain or branched C₁ -C₂₀,preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkyl groups such asmethyl, ethyl, propyl, butyl, pentyl, octyl, decyl, pentadecyl andoctadecyl groups; straight chain or branched C₁ -C₂₀, preferably C₁-C₁₀, and more preferably C₁ -C₅, alkyl groups substituted with one ormore hydroxy groups with at least one hydrogen atom in the hydroxy groupbeing optionally replaced for protection, such as hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyoctyl,hydroxydecyl, hydroxypentadecyl and hydroxyoctadecyl groups, and thesegroups with the hydroxy group being protected by a protecting group;straight chain or branched C₁ -C₂₀, preferably C₁ -C₁₀, and morepreferably C₁ -C₅, alkyl groups substituted with one or more aminogroups with at least one hydrogen atom in the amino group beingoptionally replaced for protection, such as aminomethyl, aminoethyl,aminopropyl, aminobutyl, aminopentyl, aminooctyl, aminodecyl,aminopentadecyl and aminooctadecyl groups, and these groups with theamino group being protected by a protecting group; straight chain orbranched C₁ -C₂₀, preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkylgroups with at least one hydrogen atom being replaced by a halogen atom,such as chloromethyl, fluoromethyl, bromomethyl, lodomethyl,chloroethyl, fluoroethyl, bromoethyl, iodoethyl, bromononyl,bromooctadecyl, dichloromethyl, dibromomethyl and trichloromethylgroups; straight chain or branched C₁ -C₂₀, preferably C₁ -C₁₀, and morepreferably C₁ -C₅, alkoxy groups such as methoxy, ethoxy, propyloxy,butoxy, pentoxy, octyloxy, decyloxy, pentadecyloxy and octadecyloxygroups; straight chain or branched C₁ -C₂₀, preferably C₁ -C₁₀, and morepreferably C₁ -C₅, alkoxy groups substituted with one or more hydroxygroups with at least one hydrogen atom in the hydroxy group beingoptionally replaced for protection, such as hydroxymethoxy,hydroxyethoxy, hydroxypropoxy, hydroxybutoxy, hydroxypentoxy,hydroxyoctyloxy, hydroxydecyloxy, hydroxypentadecyloxy andhydroxyoctadecyloxy groups, and these groups with the hydroxy groupbeing protected by a protecting group; and straight chain or branched C₁-C₂₀, preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkoxy groups withat least one hydrogen atom being replaced by a halogen atom, such aschloromethoxy, fluoromethoxy, bromomethoxy, iodomethoxy, chloroethoxy,fluoroethoxy, bromoethoxy, iodoethoxy, bromopentoxy, bromononyloxy andbromooctyloxy groups.

As the protecting group for hydroxy groups, there can be mentioned, forexample, aliphatic acyl groups, typical examples of which arealkylcarbonyl, cycloalkylcarbonyl and aromatic carbonyl groups such asacetyl, propionyl, valeryl, adamantoyl and 2,4,6-trimethylbenzoylgroups; halogen atoms such as chlorine and bromine atoms; benzyl groupsoptionally substituted with an alkyl group such as methyl, ethyl, propylor butyl group, or with an alkoxy group such as methoxy, ethoxy, propoxyor butoxy group; trialkylsilyl, dialkylphenylsilyl, alkyldiphenylsilyl,triphenylsilyl, aralkyldialkylsilyl, diaralkylalkylsilyl andtriaralkylsilyl groups, and these groups with at least one hydrogen atomin the aralkyl or phenyl group being replaced by a halogen atom, analkyl group, an alkoxy group or the like, such as trimethylsilyl,triethylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl,methyldibenzylsilyl, tribenzylsilyl, dimethylbutylsilyl,methyldiphenylsilyl and triphenylsilyl groups; and alkoxyalkyl groupssuch as tetrahydropyranyl, tetrahydrofuranyl, ethoxyethyl andpropoxyethyl groups.

As the protecting group for amino groups, there can be mentioned, forexample, oxycarbonyl groups such as methoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 1,1-dimethyl-2-chloroethoxycarbonyl,cyclobutoxycarbonyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl,benzyloxycarbonyl and tertiary-butoxycarbonyl groups; alkoxymethylgroups such as methoxymethyl group; phosphinyl groups such asN-diphenylphosphinyl and N-dimethylthiophosphinyl groups; sulfonylgroups such as 2,4,6-trimethylbenzenesulfonyl, toluenesulfonyl,trifluoromethylsulfonyl and methanesulfonyl groups. The amino groupprotected by a protecting group in the present invention furtherincludes one or more nitrogen atoms constituting a nitrogen-containingheterocyclic ring such as imidazolyl, benzimidazolyl, purine, pyrimidineor triazole ring.

As the nitrile (2), there can be mentioned, for example,4-oxo-4H-benzopyranyl group-containing nitriles such as5-hydroxy-2-cyano-4-oxo-4H-benzopyran,7-hydroxy-2-cyano-4-oxo-4H-benzopyran,5,7-dihydroxy-2-cyano-4-oxo-4H-benzopyran,5-methoxy-2-cyano-4-oxo-4H-benzopyran,5-ethoxy-2-cyano-4-oxo-4H-benzopyran,5-butoxy-2-cyano-4-oxo-4H-benzopyran,5-pentoxy-2-cyano-4-oxo-4H-benzopyran,6-chloro-2-cyano-4-oxo-4H-benzopyran, 2-cyano-4-oxo-4H-benzopyran,8-acetylamino-2-cyano-4-oxo-4H-benzopyran,6-acetylamino-2-cyano-4-oxo-4H-benzopyran,8-propionylamino-2-cyano-4-oxo-4H-benzopyran,6-propionylamino-2-cyano-4-oxo-4H-benzopyran,8-nonanoylamino-2-cyano-4-oxo-4H-benzopyran,6-nonanoylamino-2-cyano-4-oxo-4H-benzopyran,8-hexadecanoylamino-2-cyano-4-oxo-4H-benzopyran,6-hexadecanoylamino-2-cyano-4-oxo-4H-benzopyran,8-benzoylarnino-2-cyano-4-oxo-4H-benzopyran,6-benzoylamino-2-cyano-4-oxo-4H-benzopyran,8-(3-phenylpropionyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(3-propionyl)amino-2-cyano-4-oxo-4H-benzopyran,8-(9-phenylnonanoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(9-phenylnonanoyl)amino-2-cyano-4-oxo-4H-benzopyran,8-(16-phenylhexadecanoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(16-phenylhexadecanoyl)amino-2-cyano-4-oxo-4H-benzopyran,8-(4-methoxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(4-methoxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,8-(4-ethoxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(4-ethoxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,8-(4-propoxybenzoyl )amino-2-cyano-4-oxo-4H-benzopyran,6-(4-propoxybenzoyl )amino-2-cyano-4-oxo-4H-benzopyran,8-(4-butoxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(4-butoxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran, 8-4-(1,1-dimethylmethoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 6-4-(1,1-dimethylrmethoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 8-4-(1,1,1-trimethylmethoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 6-4-(1,1,1-trimethylrnethoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran,8-(4-octyloxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(4-octyloxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,8-(4-pentadecyloxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran,6-(4-pentadecyloxybenzoyl)amino-2-cyano-4-oxo-4H-benzopyran, 8-4-(3-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 6-4-(3-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 8-4-(4-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 6-4-(4-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 8-4-(8-phenyloctyloxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, 6-4-(8-phenyloctyloxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran,8-nitro-2-cyano-4-oxo-4H-benzopyran,6-nitro-2-cyano-4-oxo-4H-benzopyran,8-nitro-6-chloro-2-cyano-4-oxo-4H-benzopyran and8-nitro-6-bromo-2-cyano-4-oxo-4H-benzopyran; and aryl group-containingnitriles such as benzonitrile, 2-chlorobenzonitrile,3-chlorobenzonitrile, 4-chlorobenzonitrile, 2-bromobenzonitrile,3-bromobenzonitrile, 4-bromobenzonitrile, 2-fluorobenzonitrile,3-fluorobenzonitrile, 4-fluorobenzonitrile, 2-methylbenzonitrile,3-methylbenzonitrile, 4-methylbenzonitrile, 2-ethylbenzonitrile,3-ethylbenzonitrile, 4-ethylbenzonitrile, 2-propylbenzonitrile,3-propylbenzonitrile, 4-propylbenzonitrile, 2-butylbenzonitrile,3-butylbenzonitrile, 4-butylbenzonitrile, 2-octylbenzonitrile,3-octylbenzonitrile, 4-octylbenzonitrile, 2-pentadecylbenzonitrile,3-pentadecylbenzonitrile, 4-pentadecylbenzonitrile,2-benzylbenzonitrile, 3-benzylbenzonitrile, 4-benzylbenzonitrile,2-phenethylbenzonitrile, 3-phenethylbenzonitrile,4-phenethylbenzonitrile, 2-(4-phenylbutyl)benzonitrile,3-(4-phenylbutyl)benzonitrile, 4-(4-phenylbutyl)benzonitrile,2-(8-phenyloctyl)benzonitrile, 3-(8-phenyloctyl)benzonitrile,4-(8-phenyloctyl)benzonitrile, 2-(15-phenylpentadecyl)benzonitrile,3-(15-phenylpentadecyl)benzonitrile,4-(15-phenylpentadecyl)benzonitrile, 2-methoxybenzonitrile,3-methoxybenzonitrile, 4-methoxybenzonitrile, 2-ethoxybenzonitrile,3-ethoxybenzonitrile, 4-ethoxybenzonitrile, 2-propoxybenzonitrile,3-propoxybenzonitrile, 4-propoxybenzonitrile, 2-butoxybenzonitrile,3-butoxybenzonitrile, 4-butoxybenzonitrile, 2-octyloxybenzonitrile,3-octyloxybenzonitrile, 4-octyloxybenzonitrile,2-pentadecyloxybenzonitrile, 3-pentadecyloxybenzonitrile,4-pentadecyloxybenzonitrile, 2-benzyloxybenzonitrile,3-benzyloxybenzonitrile, 4-benzyloxybenzonitrile,2-phenethyloxybenzonitrile, 3-phenethyloxybenzonitrile,4-phenethyloxybenzonitrile, 2-(4-phenylbutoxy)benzonitrile,3-(4-phenylbutoxy)benzonitrile, 4-(4-phenylbutoxy)benzonitrile,2-(8-phenyloctyloxy)benzonitrile, 3-(8-phenyloctyloxy)benzonitrile,4-(8-phenyloctyloxy)benzonitrile,2-(15-phenylpentadecyloxy)benzonitrile,3-(15-phenylpentadecyloxy)benzonitrile,4-(15-phenylpentadecyloxy)benzonitrile, 2-(1-phenyl)ethoxybenzonitrile,3-(1-phenyl)ethoxybenzonitrile, 4-(1-phenyl)ethoxybenzonitrile,2-cyano-1,1'-biphenyl, 2-cyano-4'-methyl-1,1'-biphenyl,2-cyano-4'-ethyl-1,1'-biphenyl, 2-cyano-4'-propyl-1,1'-biphenyl,2-cyano-4'-butyl-1,1'-biphenyl, 2-cyano-4'-octyl-1,1'-biphenyl,2-cyano-4'-decyl-1,1'-biphenyl, 2-cyano-4'-hydroxymethyl-1,1'-bi-phenyl,2-cyano-4'-(2-hydroxy)ethyl-1,1'-biphenyl,2-cyano-4'-(3-hydroxy)propyl-1,1'-biphenyl,2-cyano-4'-(4-hydroxy)butyl-1,1'-biphenyl,2-cyano-4'-(8-hydroxy)octyl-1,1'-biphenyl,2-cyano-4'-methoxymethyl-1,1'-biphenyl,2-cyano-4'-(2-methoxy)ethyl-1,1'-biphenyl,2-cyano-4'-(3-methoxy)propyl-1,1'-biphenyl,2-cyano-4'-(4-methoxy)butyl-1,1'-biphenyl,2-cyano-4'-(8-methoxy)octyl-1,1'-biphenyl,2-cyano-4'-benzyloxymethyl-1,1'-biphenyl,2-cyano-4'-(2-benzyloxy)ethyl-1,1'-biphenyl,2-cyano-4'-(3-benzyloxy)propyl-1,1'-biphenyl,2-cyano-4'-(4-benzyloxy)butyl-1,1'-biphenyl,2-cyano-4'-(8-benzyloxy)octyl-1,1'-biphenyl, 2-cyano-4'-2-(4-methoxybenzyloxy)ethyl!-1,1'-biphen yl, 2-cyano-4'- 3-(4-methoxybenzyloxy)propyl!-1,1'-biphenyl, 2-cyano-4'-4-(4-methoxybenzyloxy)butyl!-1,1'-biphenyl, 2-cyano-4'-8-(4-methoxy-benzyloxy)octyl!-1,1'-biphenyl,2-cyano-4'-aminomethyl-1,1'-biphenyl,2-cyano-4'-(2-amino)ethyl-1,1'-biphenyl,2-cyano-4'-(3-amino)propyl-1,1'-biphenyl,2-cyano-4'-(4-amino)butyl-1,1'-biphenyl,2-cyano-4'-(8-amino)octyl-1,1'-biphenyl,2-cyano-4'-(N-mesylamino)methyl-1,1'-biphenyl,2-cyano-4'-(2-mesylamino)ethyl-1,1'-biphenyl,2-cyano-4'-(3-mesylamino)propyl-1,1'-biphenyl,2-cyano-4'-(4-mesylamino)butyl-1,1'-biphenyl,2-cyano-4'-(8-mesylamino)octyl-1,1'-biphenyl,2-cyano-4'-(benzyloxycarbonylamino)methyl-1,1'-biphenyl,2-cyano-4'-(2-benzyloxycarbonylamino)ethyl-1,1'-biphenyl,2-cyano-4'-(3-benzyloxycarbonylamino)propyl-1,1'-biphenyl,2-cyano-4'-(4-benzyloxycarbonylamino)butyl-1,1'-biphenyl,2-cyano-4'-(8-benzyloxycarbonylamino)octyl-1,1'-biphenyl,2-cyano-4'-(tertiary-butoxycarbonylamino)methyl-1,1'-biphenyl,2-cyano-4'-(2-tertiary-butoxycarbonylamino)ethyl-1,1'-biphenyl,2-cyano-4'-(3-tertiary-butoxycarbonylamino)propyl-1,1'-biphenyl,2-cyano-4'-(4-tertiary-butoxycarbonylamino)butyl-1,1'-biphenyl,2-cyano-4'-(8-tertiary-butoxycarbonylamino)octyl-1,1'-biphenyl,2-cyano-4'-chloromethyl-1,1'-biphenyl,2-cyano-4'-bromomethyl-1,1'-biphenyl, 2-cyano-4'-(2-bromo)ethyl-1,1'-biphenyl, 2-cyano-4'-(3-bromo)propyl-1,1'-biphenyl,2-cyano-4'-(4-bromo)butyl-1,1'-biphenyl,2-cyano-4'-(8-bromo)octyl-1,1'-biphenyl,2-cyano-4'-dichloromethyl-1,1'-biphenyl,2-cyano-4'-trichloromethyl-1,1'-biphenyl,2-cyano-4'-dibromomethyl-1,1'-biphenyl,2-cyano-4'-tribromomethyl-1,1'-biphenyl,2-cyano-4'-methoxy-1,1'-biphenyl, 2-cyano-4'-ethoxy-1,1'-biphenyl,2-cyano-4'-propoxy-1,1-biphenyl, 2-cyano-4'-buyoxy- 1,1'-biphenyl,2-cyano-4'-chloro-methoxy-1,1'-biphenyl and2-cyano-4'-(2-chloro)ethoxy-1,1'-biphenyl.

As the hydrazine or the salt thereof, which is used in the presentinvention, there can be mentioned anhydrous hydrazine, aqueoushydrazine, and hydrazine salts such as hydrazine hydrochloride andhydrazine sulfate.

As the nitrous acid compound (3) used in the present invention, therecan be mentioned nitrous acid; alkali metal nitrites such as sodiumnitrite and potassium nitrite, and alkaline earth metal nitrites such asbarium nitrite; C₁ -C₂₀, preferably C₁ -C₁₀, and more preferably C₁ -C₅,alkyl nitrites such as ethyl nitrite and isoamyl nitrite.

According to the production process of the present invention, tetrazolecompound (1) can be produced by reacting nitrioe (2) with hydrazine or asalt thereof in the presence of a catalyst, followed by reaction withnitrous acid compound (3).

The reaction of nitrile (2) with hydrazine or a salt thereof in thepresence of a catalyst can be effected as follows.

The reaction of nitrile (2) with hydrazine or a salt thereof in thepresence of a catalyst makes it possible to obtain an amidrazone ofgeneral formula (6):

    R.sup.1 C(=NH)NHNH.sub.2                                   (6)

wherein R¹ is as defined above, which corresponds to the amide (5) whereR⁵ is an NH group and R⁶ is an NHNH₂ group as the productionintermediate of the present invention. The arnidrazone (6) istautomerized into an isomerized aridrazone of general formula (9):

    R.sup.1 C(=NNH.sub.2)NH.sub.2                              (9)

wherein R¹ is as defined above, which is a tautomer thereof. In thepresent invention, both are represented by the term "amidrazone (6)".

The amount of hydrazine or a salt thereof, which is to be used, isusually from 1 to 20 moles, relative to nitrile (2).

As the catalyst used in the above reaction, there can be mentioned thosewhich enhance the reactivity of nitrile (2). For example, there can bementioned alkoxides such as sodium methoxide and sodium ethoxide; alkalimetals such as sodium and potassium; alkali metal amides such as sodiumamide, lithium amide and sodium hydrazide; alkali metal or alkalineearth metal hydrides such as lithium hydride, sodium hydride and calciumhydride; sulfides or salts thereof, such as hydrogen sulfide,methylmercaptan, ethylmercaptan, butylmercaptan, sodium sulfide andammonium sulfide; thiocyanates such as potassium thiocyanate; organicamines including pyridine compounds such as pyridine, picoline and2-methyl-5-ethylpyridine, alkylamines such as triethylamine, methylamineand dimethylamine, aromatic ainines such as dimethylaniline anddimethylaminopyridine, and diamines, typical examples of which arealkylenediamines such as tetramethylethylenediamine and aromaticdiamines such as phenylenediamine; and phase transfer catalysts, typicalexamples of which are organic quaternary ammonium salts such astetrabutylammonium bromide, benzyltriethylammonium chloride andcetylpyridinium chloride. These can be used alone or as a mixture of twoor more kinds of catalysts. Particularly preferred are hydrogen sulfide;mixtures of hydrogen sulfide and alkylamines such as dimethylamine andtriethylamine; and alkoxides derived from lower alcohols, such as sodiummethoxide and sodium ethoxide. The amount of catalyst to be used,although it may vary with the kind of catalyst used, is usually from0.001 to 5 moles, preferably from 0.01 to 5 moles, and more preferablyfrom 0.1 to 5 moles, relative to nitrile (2).

The above reaction is usually effected in the presence of an organicsolvent. As the solvent used, there can be mentioned those which areinert to hydrazine or salts thereof, for example, hydrocarbons such asbenzene, toluene and hexane; halogenated hydrocarbons such asdichloromethane, dichloroethane and chlorobenzene; nitrated hydrocarbonssuch as nitrobenzene and nitromethane; ethers such as diethyl ether andtetrahydrofuran; amides such as dimethylformamide; and alcohols such asmethanol and ethanol. These can be used alone or as a mixture of two ormore kinds of solvents. The amount of solvent to be used, although itcan be appropriately determined, is usually from 1 to 100 times as muchas the weight of nitrile (2).

The method and order for the addition of nitrile (2) and hydrazine or asalt thereof are not particularly limited, and usually, hydrazine or asalt thereof may be added to a mixture of nitrile (2), a catalyst and asolvent.

The reaction temperature is usually from -78° to +150° C., preferablyfrom -50° to +100° C. The completion of the reaction can be monitored byan analytical method such as liquid chromatography. Usually, thedisappearance of nitrile (2) can be considered as the end point of thereaction.

After completion of the reaction, amidrazone (6) can be isolated by anordinary procedure such as extraction or filtration, or can be used inthe next step without isolation. Alternatively, amidrazone (6) can beisolated as a stable onium salt by the addition of an acid such asconcentrated hydrochloric acid or acetic acid to the reaction mixture,and then used in the next step. In this case, the amount of acid to beadded is usually from 1 to 5 moles, relative to amidrazone (6), and theisolation can be usually carried out by filtration.

As the amidrazone (6) thus obtained, there can be mentioned, forexample, 4-oxo-4H-benzopyranyl group-containing amidrazones such as(5-hydroxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(7-hydroxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(5,7-dihydroxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(5-methoxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(5-ethoxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(5-butoxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(5-pentoxy-4-oxo-4H-benzopyran-2-yl)amidrazone,(6-chloro-4-oxo-4H-benzopyran-2-yl)amidrazone,(4-oxo-4H-benzopyran-2-yl)amidrazone,(8-acetylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(6-acetylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(8-propionylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(6-propionylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(8-nonanoylamino-4-oxo-4H-benzopyran-2-yl )amidrazone,(6-nonanoylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(8-hexadecanoylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(6-hexadecanoylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(8-benzoylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,(6-benzoylamino-4-oxo-4H-benzopyran-2-yl)amidrazone,8-(3-phenylpropionyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(3-propionyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-(9-phenylnonanoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(9-phenylnonanoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-(16-phenylhexadecanoyl) amino-4-oxo-4H -benzopyran-2-yl!amidrazone,6-(16-phenylhexadecanoyl) amino-4-oxo-4H -benzopyran-2-yl!amidrazone,8-(4-methoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(4-methoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-(4-ethoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(4-ethoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!-amidrazone,8-(4-propoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(4-propoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-(4-butoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(4-butoxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone, 8-4-(1,1-dimethylmethoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-4-(1,1-dimethylmethoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-4-(1,1,1-trimethylmethoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-4-(1,1,1-trimethylmethoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-(4-octyloxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(4-octyloxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,8-(4-pentadecyloxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone,6-(4-pentadecyloxybenzoyl)amino-4-oxo-4H-benzopyran-2-yl!amidrazone, 8-4-(3-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone, 6-4-(3-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone, 8-4-(4-phenylbutoxy)benzoyl!-amino-4-oxo-4H-benzopyran-2-yl!amidrazone, 6-4-(4-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone, 8-4-(8-phenyloctyloxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amaidrazone,6-4-(8-phenyloctyloxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone,(8-nitro-4-oxo-4H-benzopyran-2-yl)amidrazone,(6-nitro-4-oxo-4H-benzopyran-2-yl)amidrazone,(8-nitro-6-chloro-4-oxo-4H-benzopyran-2-yl)amidrazone and(8-nitro-6-bromo-4-oxo-4H-benzopyran-2-yl)amidrazone; and arylgroup-containing amidrazones such as benzonitrile,2-chlorobenzarnidrazone, 3-chlorobenzamidrazone, 4-chlorobenzamidrazone,2-bromobenzamidrazone, 3-bromobenzamindrazone, 4-bromobenzamidrazone,2-fluorobenzamidrazone, 3-fluorobenzamidrazone, 4-fluorobenzamidrazone,2-methylbenzamidrazone, 3-methylbenzamidrazone, 4-methylbenzarnidrazone,2-ethylbenzamidrazone, 3-ethylbenzamidrazone, 4-ethylbenzamidrazone,2-propylbenzamidrazone, 3-propylbenzamidrazone, 4-propylbenzamnidrazone,2-butylbenzamidrazone, 3-butylbenzamidrazone, 4-butylbenzamidrazone,2-octylbenzamidrazone, 3-octylbenzarmi drazone, 4-octylbenzamidrazone,2-pentadecylbenzarnidrazone, 3-pentadecylbenzamidrazone,4-pentadecylbenzarnidrazone, 2-benzylbenzamidrazone,3-benzylbenzamidrazone, 4-benzylbenzamidrazone,2-phenethylbenzamidrazone, 3-phenethylbenzamidrazone,4-phenethylbenzamidrazone, 2-(4-phenylbutyl)benzamidrazone,3-(4-phenylbutyl)benzamidrazone, 4-(4-phenylbutyl)benzamidrazone,2-(8-phenyloctyl)benzamidrazone, 3-(8-phenyloctyl)benzamidrazone,4-(8-phenyloctyl)benzamidrazone, 2-(15-phenylpentadecyl)benzamidrazone,3-(15-phenylpentadecyl)benzamidrazone,4-(15-phenylpentadecyl)benzamidrazone, 2-methoxybenzarmidrazone,3-methoxybenzamidrazone, 4-methoxybenzamidrazone,2-ethoxybenzamidrazone, 3-ethoxybenzamidrazone, 4-ethoxybenzamidrazone,2-propoxybenzamidrazone, 3-propoxybenzamidrazone,4-propoxybenzamnidrazone, 2-butoxybenzamidrazone,3-butoxybenzamidrazone, 4-butoxybenzamidrazone,2-octyloxybenzamidrazone, 3-octyloxybenzamidrazone,4-octyloxybenzamidrazone, 2-pentadecyloxybenzamidrazone,3-pentadecyloxybenzamidrazone, 4-pentadecyloxybenzamidrazone,2-benzyloxybenzamidrazone, 3-benzyloxybenzamidrazone,4-benzyloxybenzamidrazone, 2-phenethyloxybenzamidrazone,3-phenethyloxybenzamidrazone, 4-phenethyloxybenzamidrazone,2-(4-phenylbutoxy)benzamidrazone, 3-(4-phenylbutoxy)benzamidrazone,4-(4-phenylbutoxy)benzamidrazone, 2-(8-phenyloctyloxy)benzamidrazone,3-(8-phenyloctyloxy)benzamidrazone, 4-(8-phenyloctyloxy)benzamidrazone,2-(15-phenylpentadecyloxy)benzamidrazone,3-(15-phenylpentadecyloxy)benzamidrazone,4-(15-phenylpentadecyloxy)benzamidrazone,2-(1-phenyl)ethoxybenzamidrazone, 3-(1-phenyl)ethoxybenzamidrazone,4-(1-phenyl)ethoxybenzamidrazone, (1,1'-biphen-2-yl)amidrazone,(4'-methyl-1,1'-biphen-2-yl)amidrazone,(4'-ethyl-1,1'-biphen-2-yl)amidrazone,(4'-propyl-1,1'-biphen-2-yl)amidrazone, (4'-butyl-1,1'-biphen-2-yl)amidrazone, (4'-octyl-1,1'-biphen-2-yl)amindrazone,(4'-decyl-1,1'-biphen-2-yl)amidrazone,(4'-hydroxymethyl-1,1'-biphen-2-yl)amidrazone,4'-(2-hydroxy)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-hydroxy)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-hydroxy)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-hydroxy)octyl-1,1'-biphen-2-yl!amidrazone,(4'-methoxymethyl-1,1'-biphen-2-yl)amidrazone,4'-(2-methoxy)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-methoxy)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-methoxy)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-methoxy)octyl-1,1'-biphen-2-yl!amidrazone,(4'-benzyloxymethyl-1,1'-biphen-2-yl)amidrazone,4'-(2-benzyloxy)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-benzyloxy)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-benzyloxy)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-benzyloxy)octyl-1,1'-biphen-2-yl!-amidrazone, 4'-2-(4-methoxybenzyloxy)ethyl!-1,1 '-biphen-2-yl!amidrazone, 4'-3-(4-methoxybenzyloxy)propyl!-1,1'-biphen-2-yl!amidrazone, 4'-4-(4-methoxybenzyloxy)butyl!-1,1'-biphen-2-yl!amidrazone, 4'-8-(4-methoxybenzyloxy)octyl!-1,1'-biphen-2-yl!amidrazone,(4'-aminomethyl-1,1'-biphen-2-yl)amidrazone,4'-(2-amino)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-amino)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-amino)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-amino)octyl-1,1'-biphen-2-yl!amidrazone,4'-(N-mesylamino)methyl-1,1'-biphen-2-yl!amidrazone,4'-(2-mesylamino)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-mesylamino)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-mesylamino)butyl-1,1'-biphen-2-yl!amnidrazone,4'-(8-mesylamino)octyl-1,1'-biphen-2-yl!amidrazone,4'-(benzyloxycarbonylamino)methyl-1,1'-biphen-2-yl!amidrazone,4'-(2-benzyloxycarbonylamino)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-benzyloxy-carbonylamino)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-benzyloxycarbonylamino)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-benzyloxycarbonylamino)octyl-1,1'-biphen-2-yl!amidrazone,4'-(tertiary-butoxycarbonylamino)methyl-1,1'-biphen-2-yl!amidrazone,4'-(2-tertiary-butoxycarbonylamino)ethyl-1,1'-biphen-2-yl!amidrazone,4'-(3-tertiary-butoxycarbonylamino)propyl-1,1'-biphen-2-yl!amid razone,4'-(4-tertiary-butoxycarbonylamino)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-tertiary-butoxycarbonylamnino)octyl-1,1'-biphen-2-yl!amidrazone,(4'-chloromethyl-1,1'-biphen-2-yl)amidrazone,(4'-bromomethyl-1,1'-biphen-2-yl)amidrazone,4'-(2-bromo)ethyl-1,1'-biphen-2-yl!-arnidrazone,4'-(3-bromo)propyl-1,1'-biphen-2-yl!amidrazone,4'-(4-bromo)butyl-1,1'-biphen-2-yl!amidrazone,4'-(8-bromo)octyl-1,1'-biphen-2-yl!amidrazone,(4'-dichloromethyl-1,1'-biphen-2-yl)amidrazone,(4'-trichloromethyl-1,1'-biphen-2-yl)amidrazone,(4'-dibromomethyl-1,1'-biphen-2-yl)amidrazone,(4'-tribromomethyl-1,1'-biphen-2-yl)amidrazone,(4'-methoxy-1,1'-biphen-2-yl)amidrazone,(4'-ethoxy-1,1'-biphen-2-yl)amidrazone,(4'-propoxy-1,1'-biphen-2-yl)amidrazone,(4'-butoxy-1,1'-biphen-2-yl)amidrazone,(4'-chloromethoxy-1,1'-biphen-2-yl)amidrazone and4'-(2-chloro)ethoxy-1,1'-biphen-2-yl!amidrazone.

The reaction of amnidrazone (6) or a salt thereof with nitrous acidcompound (3) can be effected as follows.

The reaction of amidrazone (6) or a salt thereof with nitrous acidcompound makes it possible to produce tetrazole compound (1).

The amount of nitrous acid compound (3) to be used is usually from 1 to50 moles, relative to amidrazone (6) or a salt thereof.

When an alkali metal nitrite or an alkaline earth metal nitrite is usedas the nitrous acid compound (3), an inorganic or organic acid such ashydrochloric acid, acetic acid or methanesulfonic acid is usually usedtogether, and the amount thereof is usually from 1 to 100 moles,relative to nitrous acid compound (3).

The above reaction is usually effected in a solvent. As the solvent tobe used, there can be mentioned hydrocarbons such as benzene, tolueneand hexane; halogenated hydrocarbons such as dichloromethane,dichloroethane and chlorobenzene; nitrated hydrocarbons such asnitrobenzene and nitromethane; ethers such as diethyl ether andtetrahydrofuran; amides such as dimethylformamide; alcohols such asmethanol and ethanol; and organic acids such as acetic acid and butyricacid. These can be used alone or as a mixture of two or more kinds ofsolvents. The amount of solvent to be used is usually from 3 to 200times as much as the weight of amidrazone (6) or a salt thereof.

The method and order for the addition of amidrazone (6) or a saltthereof, a nitrous acid compound (and an organic or inorganic acid) anda solvent are not particularly limited, and usually, nitrous acidcompound (3) may be added to a mixture of amidrazone (6) or a saltthereof, an acid and a solvent.

The reaction temperature is from -78° to +150° C., preferably from -50°to +50° C.

The end point of the reaction can be monitored by an analytical methodsuch as liquid chromatography, and tetrazole compound (1) can beobtained, for example, by an ordinary work up such as extraction orfiltration, and can also be purified, if necessary, by an ordinarytechnique such as recrystallization.

As the tetrazole compound thus obtained, there can be mentioned, forexample, 4-oxo-4H-benzopyranyl group-containing tetrazole compounds suchas 5-hydroxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,7-hydroxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,5,7-dihydroxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,5-methoxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,5-ethoxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,5-butoxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,5-pentoxy-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-chloro-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-acetylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-acetylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-propionylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-propionylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-nonanoylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-nonanoylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-hexadecanoylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-hexadecanoylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-benzoylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-benzoylamino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(3-phenylpropionyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(3-propionyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(9-phenylnonanoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(9-phenylnonanoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(16-phenylhexadecanoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(16-phenylhexadecanoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(4-methoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(4-methoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(4-ethoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(4-ethoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(4-propoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(4-propoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(4-butoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(4-butoxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran, 8-4-(1,1-dimethylmethoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-4-(1,1-dimethylmethoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-4-(1,1,1-trimethylmethoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-4-(1,1,1-trimethylmethoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(4-octyloxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(4-octyloxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-(4-pentadecyloxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-(4-pentadecyloxybenzoyl)amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-4-(3-phenylbutoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-4-(3-phenylbutoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-4-(4-phenylbutoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-4-(4-phenylbutoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-4-(8-phenyloctyloxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-4-(8-phenyloctyloxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-nitro-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,6-nitro-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran,8-nitro-6-chloro-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran and8-nitro-6-bromo-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran; and arylgroup-containing tetrazole compounds such as (tetrazol-5-yl)benzene,2-chloro-(tetrazol-5-yl)benzene, 3-chloro-(tetrazol-5-yl)benzene,4-chloro-(tetrazol-5-yl)benzene, 2-bromo-(tetrazol-5-yl)benzene,3-bromo-(tetrazol-5-yl)benzene, 4-bromo-(tetrazol-5-yl)benzene,2-fluoro-(tetrazol-5-yl)benzene, 3-fluoro-(tetrazol-5-yl)benzene,4-fluoro-(tetrazol-5-yl)benzene, 2-methyl-(tetrazol-5-yl)benzene,3-methyl-(tetrazol-5-yl)benzene, 4-methyl-(tetrazol-5-yl)benzene,2-ethyl-(tetrazol-5-yl)benzene, 3-ethyl-(tetrazol-5-yl)benzene,4-ethyl-(tetrazol-5-yl)benzene, 2-propyl-(tetrazol-5-yl)benzene,3-propyl-(tetrazol-5-yl)benzene, 4-propyl-(tetrazol-5-yl)benzene,2-butyl-(tetrazol-5-yl)benzene, 3-butyl-(tetrazol-5-yl)benzene,4-butyl-(tetrazol-5-yl)benzene, 2-octyl-(tetrazol-5-yl)benzene,3-octyl-(tetrazol-5-yl)benzene, 4-octyl-(tetrazol-5-yl)benzene,2-pentadecyl-(tetrazol-5-yl)benzene,3-pentadecyl-(tetrazol-5-yl)benzene,4-pentadecyl-(tetrazol-5-yl)benzene, 2-benzyl-(tetrazol-5-yl)benzene,3-benzyl-(tetrazol-5-yl)benzene, 4-benzyl-(tetrazol-5-yl)benzene,2-phenethyl-(tetrazol-5-yl)benzene, 3-phenethyl-(tetrazol-5-yl)benzene,4-phenethyl-(tetrazol-5-yl)benzene,2-(4-phenylbutyl)-(tetrazol-5-yl)benzene,3-(4-phenylbutyl)-(tetrazol-5-yl)benzene,4-(4-phenylbutyl)-(tetrazol-5-yl)benzene,2-(8-phenyloctyl)-(tetrazol-5-yl)benzene,3-(8-phenyloctyl)-(tetrazol-5-yl)benzene,4-(8-phenyloctyl)-(tetrazol-5-yl)benzene,2-(15-phenylpentadecyl)-(tetrazol-5-yl)benzene,3-(15-phenylpentadecyl)-(tetrazol-5-yl)benzene, 4-(15-phenylpentadecyl)-(tetrazol-5-yl)benzene,2-methoxy-(tetrazol-5-yl)benzene, 3-methoxy-(tetrazol-5-yl)benzene,4-methoxy-(tetrazol-5-yl)benzene, 2-ethoxy-(tetrazol-5-yl)benzene,3-ethoxy-(tetrazol-5-yl)benzene, 4-ethoxy-(tetrazol-5-yl)benzene,2-propoxy-(tetrazol-5-yl)benzene, 3-propoxy-(tetrazol-5-yl)benzene,4-propoxy-(tetrazol-5-yl)benzene, 2-butoxy-(tetrazol-5-yl)benzene,3-butoxy-(tetrazol-5-yl)benzene, 4-butoxy-(tetrazol-5-yl)benzene,2-octyloxy-(tetrazol-5-yl)benzene, 3-octyloxy-(tetrazol-5-yl)benzene,4-octyloxy-(tetrazol-5-yl)benzene,2-pentadecyloxy-(tetrazol-5-yl)benzene,3-pentadecyloxy-(tetrazol-5-yl)benzene,4-pentadecyloxy-(tetrazol-5-yl)benzene,2-benzyloxy-(tetrazol-5-yl)benzene, 3-benzyloxy-(tetrazol-5-yl)benzene,4-benzyloxy-(tetrazol-5-yl)benzene,2-phenethyloxy-(tetrazol-5-yl)benzene,3-phenethyloxy-(tetrazol-5-yl)benzene,4-phenethyloxy-(tetrazol-5-yl)benzene,2-(4-phenylbutoxy)-(tetrazol-5-yl)benzene,3-(4-phenylbutoxy)-(tetrazol-5-yl)benzene,4-(4-phenylbutoxy)-(tetrazol-5-yl)benzene,2-(8-phenyloctyloxy)-(tetrazol-5-yl)benzene,3-(8-phenyloctyloxy)-(tetrazol-5-yl)benzene,4-(8-phenyloctyloxy)-(tetrazol-5-yl)benzene,2-(15-phenylpentadecyloxy)-(tetrazol-5-yl)benzene,3-(15-phenylpentadecyloxy)-(tetrazol-5-yl)benzene,4-(15-phenylpentadecyloxy)-(tetrazol-5-yl)benzene,2-(1-phenyl)ethoxy-(tetrazol-5-yl)benzene,3-(1-phenyl)ethoxy-(tetrazol-5-yl)benzene,4-(1-phenyl)ethoxy-(tetrazol-5-yl)benzene,2-(tetrazol-5-yl)-1,1'-biphenyl,2(tetrazol-5-yl)-4'-methyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-decyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-hydroxymethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-hydroxy)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-hydroxy)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-hydroxy)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-hydroxy)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-methoxymethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-methoxy)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-methoxy)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-methoxy)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-methoxy)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-benzyloxymethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-benzyloxy)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-benzyloxy)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-benzyloxy)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-benzyloxy)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'- 2-(4-methoxybenzyloxy)ethyl!-1,1'-biphenyl,2-(tetrazol-5-yl)-4'- 3-(4-methoxybenzyloxy)propyl!-1,1'-biphenyl,2-(tetrazol-5-yl)-4'- 4-(4-methoxybenzyloxy)butyl!-1,1'-biphenyl,2-(tetrazol-5-yl)-4'- 8-(4-methoxybenzyloxy)octyl!-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-aminomethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-amino)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-amino)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-amino)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-amino)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(N-mesylamino)methyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-mesylamino)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-mesylamino)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-mesylamino)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-mesylamino)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(benzyloxycarbonylamino)methyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-benzyloxycarbonylamino)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-benzyloxycarbonylamino)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-benzyloxycarbonylamino)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-benzyloxycarbonylamino)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(tertiary-butoxycarbonylamino)methyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-tertiary-butoxycarbonylamino)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-tertiary-butoxycarbonylamino)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-tertiary-butoxycarbonylamino)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-tertiary-butoxycarbonylamino)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-chloromethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-bromomethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(2-bromo)ethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(3-bromo)propyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(4-bromo)butyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-(8-bromo)octyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-dichloromethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-trichloromethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-dibromomethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-tribromomethyl-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-methoxy-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-ethoxy-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-propoxy-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-butoxy-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-chloromethoxy-1,1-biphenyl and2-(tetrazol-5-yl)-4'-(2-chloro)ethoxy-1,1'-biphenyl.

The tetrazole compound (1) can also be produced by reacting nitrile (2)with hydrogen sulfide, followed by reaction with alkyl halide (4), withhydrazine or a salt thereof, and then with nitrous acid compound (3).

The reaction of nitrile (2) with hydrogen sulfide can be effected asfollows.

The reaction of nitrile (2) with hydrogen sulfide makes it possible toobtain a thioamide of general formula (7):

    R.sup.1 C(=S)NH.sub.2                                      (7)

wherein R¹ is as defined above, which corresponds to amide (5) where R⁵is a sulfur atom and R⁶ is an NH₂ group as the production intermediateof the present invention.

The amount of hydrogen sulfide to be used is usually from 1 to 100moles, preferably from 1 to 50 moles, and more preferably 1 to 10 moles,relative to nitrile (2). The above reaction may be effected with theaddition of a base as a catalyst, typical examples of which arealkylamines such as triethylamine, tributylamine and dimethylamine. Theamount thereof is usually from 1 to 20 moles, relative to nitrile (2).

The above reaction is usually effected in the presence of an organicsolvent. As the solvent to be used, there can be mentioned hydrocarbonssuch as benzene, toluene and hexane; halogenated hydrocarbons such asdichloromethane, dichloroethane and chlorobenzene; nitrated hydrocarbonssuch as nitrobenzene and nitromethane; ethers such as diethyl ether andtetrahydrofuran; amides such as dimethylformamide; and alcohols such asmethanol and ethanol. These can be used alone or as a mixture of two ormore kinds of solvents. The amount of solvent to be used, although itcan be appropriately determined, is usually from 1 to 100 times as muchas the weight of nitrile (2).

The method and order for the addition of nitrile (2), hydrogen sulfide(and a base) and a solvent are not particularly limited, and usually,hydrogen sulfide may be added to a mixture of nitrile (2), a base and asolvent.

The reaction temperature is usually from -78° to +150° C., preferablyfrom -50° to +100° C. The completion of the reaction can be monitored byan analytical method such as liquid chromatography. Usually, thedisappearance of the nitrile can be considered as the end point of thereaction.

After completion of the reaction, thioanide (7) can be isolated, forexample, by an ordinary procedure such as extraction or filtration, orcan also be used in the next step without isolation.

As the thioamide (7) thus obtained, there can be mentioned, for example,4-oxo-4H-benzopyranyl group-containing thioarnides such as5-hydroxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,7-hydroxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,5,7-dihydroxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,5-methoxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,5-ethoxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,5-butoxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,5-pentoxy-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-chloro-2-thiocarbamoyl-4-oxo-4H-benzopyran,2-thiocarbamoyl-4-oxo-4H-benzopyran,8-acetylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-acetylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-propionylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-propionylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-nonanoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-nonanoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-hexadecanoylarnino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-hexadecanoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-benzoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-benzoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(3-phenylpropionyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(3-propionyl)arrino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(9-phenylnonanoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(9-phenylnonanoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(16-phenylhexadecanoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(16-phenylhexadecanoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(4-methoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(4-methoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(4-ethoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(4-ethoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(4-propoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(4-propoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(4-butoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(4-butoxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-4-(1,1-dimethylmethoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-4-(1,1-dimethylmethoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-4-(1,1,1-trimethylmethoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-4-(1,1,-trimethylmethoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(4-octyloxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(4-octyloxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-(4-pentadecyloxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-(4-pentadecyloxybenzoyl)amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-4-(3-phenylbutoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 6-4-(3-phenylbutoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-4-(4-phenylbutoxy)benzoyl!amino-2-thocarbamoyl-4-oxo-4H-benzopyran, 6-4-(4-phenylbutoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-4-(8-phenyloctyloxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-4-(8-phenyloctyloxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-nitro-2-thiocarbamoyl-4-oxo-4H-benzopyran,6-nitro-2-thiocarbamoyl-4-oxo-4H-benzopyran,8-nitro-6-chloro-2-thiocarbamoyl-4-oxo-4H-benzopyran and8-nitro-6-bromo-2-thiocarbamoyl-4-oxo-4H-benzopyran; and arylgroup-containing thioamides such as thiobenzamide,2-chloro-thiobenzamide, 3-chlorothiobenzamide, 4-chlorothiobenzamide,2-bromothiobenzamide, 3-bromothiobenzamide, 4-bromothiobenzamide,2-fluorothiobenzamide, 3-fluorothiobenzamide, 4-fluorothiobenzamide,2-methylthiobenzamide, 3-methylthiobenzamide, 4-methylthiobenzamide,2-ethylthiobenzamide, 3-ethylthiobenzamide, 4-ethylthiobenzamide,2-propylthiobenzamide, 3-propylthiobenzamnide, 4-propylthiobenzamide,2-butylthiobenzamide, 3-butylthiobenzamide, 4-butylthiobenzamide,2-octylthiobenzamide, 3-octylthiobenzamide, 4-octylthiobenzamide,2-pentadecylthiobenzamide, 3-pentadecylthiobenzamide,4-pentadecylthiobenzamide, 2-benzylthiobenzamide, 3-benzylthiobenzamide,4-benzylthiobenzamide, 2-phenethylthiobenzarmide,3-phenethylthiobenzamnide, 4-phenethylthiobenzamide,2-(4-phenylbutyl)thiobenzamide, 3-(4-phenylbutyl)thiobenzamide,4-(4-phenylbutyl)thiobenzamide, 2-(8-phenyloctyl)thiobenzamide,3-(8-phenyloctyl)thiobenzamide, 4-(8-phenyloctyl)thiobenzamide,2-(15-phenylpentadecyl)thiobenzamide,3-(15-phenylpentadecyl)thiobenzamide,4-(15-phenylpentadecyl)thiobenzamide, 2-methoxythiobenzamide,3-methoxythiobenzarnide, 4-methoxythiobenzarnide, 2-ethoxythiobenzamide,3 -ethoxythiobenzamide, 4-ethoxythiobenzamide, 2-propoxythiobenzamide,3-propoxythiobenzamide, 4-propoxythiobenzamide, 2-butoxythiobenzamide,3-butoxythiobenzamide, 4-butoxythiobenzamnide, 2-octyloxythiobenzamide,3-octyloxythiobenzamide, 4-octyloxythiobenzamide,2-pentadecyloxythiobenzamide, 3-pentadecyloxythiobenzarmide,4-pentadecyloxythiobenzamide, 2-benzyloxythiobenzamide,3-benzyloxythiobenzamide, 4-benzyloxythiobenzamide,2-phenethyloxythiobenzamide, 3-phenethyloxythiobenzamide,4-phenethyloxythiobenzamide, 2-(4-phenylbutoxy)thiobenzamide,3-(4-phenylbutoxy)thiobenzarmide, 4-(4-phenylbutoxy)thiobenzarmide,2-(8-phenyloctyloxy)thiobenzamide, 3-(8-phenyloctyloxy)thiobenzamide,4-(8-phenyloctyloxy)thiobenzamide,2-(15-phenylpentadecyloxy)thiobenzarnide,3-(15-phenylpentadecyloxy)thiobenzamide,4-(15-phenylpentadecyloxy)thiobenzamide,2-(1-phenyl)ethoxythiobenzamide, 3-(1-phenyl)ethoxythiobenzamide,4-(1-phenyl)ethoxythiobenzamide, 2-thiocarbamoyl-1,1'-biphenyl,2-thiocarbamoyl-4'-methyl-1,1'-biphenyl,2-thiocarbamoyl-4'-ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-butyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-octyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-decyl-1,1'-biphenyl,2-thiocarbamoyl-4'-hydroxymethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-hydroxy)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-hydroxy)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-hydroxy)butyl-1'-biphenyl,2-thiocarbamoyl-4'-(8-hydroxy)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-methoxymethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-methoxy)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-methoxy)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-methoxy)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-methoxy)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-benzyloxymethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-benzyloxy)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-benzyloxy)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-benzyloxy)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-benzyloxy)octyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-2-(4-methoxybenzyloxy)ethyl!-1,1'-biphenyl, 2-thiocarbamoyl-4'-3-(4-methoxybenzyloxy)propyl!-1,1'-biphenyl, 2-thiocarbamoyl-4'-4-(4-methoxybenzyloxy)butyl!-1,1'-biphenyl, 2-thiocarbamoyl-4'-8-(4-methoxybenzyloxy)octyl!-1,1'-biphenyl,2-thiocarbamoyl-4'-aminomethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-amino)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-amino)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-amino)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-amino)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(N-mesylamino)methyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-mesylamino)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-mesylamino)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-mesylamino)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-mesylamino)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(benzyloxycarbonylamino)methyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-benzyloxycarbonylamino)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-benzyloxycarbonylamino)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-benzyloxycarbonylamino)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-benzyloxycarbonylamino)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(tertiary-butoxycarbonylarmino)methyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-tertiary-butoxycarbonylamino)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-tertiary-butoxycarbonylamino)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-tertiary-butoxycarbonylamino)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-tertiary-butoxycarbonylamino)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-chloromethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-bromomethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(2-bromo)ethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(3-bromo)propyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(4-bromo)butyl-1,1'-biphenyl,2-thiocarbamoyl-4'-(8-bromo)octyl-1,1'-biphenyl,2-thiocarbamoyl-4'-dichloromethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-trichloromethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-dibromomethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-tribromomethyl-1,1'-biphenyl,2-thiocarbamoyl-4'-methoxy-1,1'-biphenyl,2-thiocarbamoyl-4'-ethoxy-1,1'-biphenyl,2-thiocarbamoyl-4'-propoxy-1,1'-biphenyl,2-thiocarbamoyl-4'-butoxy-1,1'-biphenyl,2-thiocarbamoyl-4'-chloromethoxy-1,1'-biphenyl and2-thiocarbamoyl-4'-(2-chloro)ethoxy-1,1'-biphenyl.

The reaction of thioamide (7) with alkyl halide (4) can be effected asfollows.

The reaction of thioamide (7) with alkyl halide (4) makes it possible toobtain a hydrogen halide salt of an isothioamide of general formula 8:

    R.sup.1 (=NH)SR.sup.4                                      (8)

wherein R¹ and R⁴ are as defined above, which corresponds to amide (5)where R⁵ is an NH group and R⁶ is an SR⁴ group as the productionintermediate of the present invention.

As the alkyl halide (4) to be used, there can be mentioned, for example,C₁ -C₂₀, preferably C₁ -C₁₀, and more preferably C₁ -C₅, alkyl halidessuch as methyl iodide, ethyl iodide, butyl iodide, butyl bromide, pentylbromide and pentyl iodide. The amount thereof may be usually 1 mole ormore, preferably from about 1 to about 5 moles, relative to thioamide(7).

The above reaction is usually effected in an organic solvent. As such asolvent, there can be mentioned, for example, hydrocarbons such asbenzene, toluene and hexane; halogenated hydrocarbons such asdichloromethane, dichloroethane and chlorobenzene; nitrated hydrocarbonssuch as nitrobenzene and nitromethane; ethers such as diethyl ether andtetrahydrofuran; amides such as dimethylformamide; alcohols such asmethanol and ethanol; and ketones such as acetone, methyl ethyl ketoneand methyl isobutyl ketone. These can be used alone or as a mixture oftwo or more kinds of solvents. The amount of solvent to be used can beappropriately determined.

The method and order for the addition of thioamide (7), alkyl halide (4)and a solvent are not particularly limited, and usually, alkyl halide(4) may be added to a mixture of thioamide (7) and a solvent.

The reaction temperature is usually from -78° to +150° C., preferablyfrom -50° to +100° C. The completion of the reaction can be monitored byan analytical method such as liquid chromatography. Usually, thedisappearance of thioamide (7) can be considered as the end point of thereaction.

After completion of the reaction, a hydrogen halide salt of isothioamide(8) can be isolated, for example, by an ordinary procedure such asextraction or filtration, or can also be used in the next step withoutisolation.

As the hydrogen halide salt of isothioamide (8) thus obtained, there canbe mentioned, for example, 4-oxo-4H-benzopyranyl group-containingisothioamides such as5-hydroxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,7-hydroxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,5,7-dihydroxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,5-methoxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,5-ethoxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,5-butoxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,5-pentoxy-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-chloro-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-acetylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-acetylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-propionylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-propionylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-nonanoylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-nonanoylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-hexadecanoylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-hexadecanoylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-benzoylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-benzoylamino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(3-phenylpropionyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(3-propionyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(9-phenylnonanoyl)amino-2-(S-methyl)lsothlocarbamoyl-4-oxo-4H-benzopyran,6-(9-phenylnonanoyl)amino-2-(S-methyl)isothlocarbamoyl-4-oxo-4H-benzopyran,8-(16-phenylhexadecanoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(16-phenylhexadecanoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(4-methoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(4-methoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(4-ethoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(4-ethoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(4-propoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(4-propoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(4-butoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(4-butoxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-4-(1,1-dimethylmethoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-4-(1,1-dimethylmethoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8- 4-(1,1,1-trimethylmethoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4 H-benzopyran, 6-4-(1,1,1,-trimethylmethoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(4-octyloxybenzoyl)armino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(4-octyloxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-(4-pentadecyloxybenzoyl)amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-(4-pentadecyloxybenzoyl)amino-2-(S-methyl)isothlocarbamoyl-4-oxo-4H-benzopyran,8-4-(3-phenylbutoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-4-(3-phenylbutoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-4-(4-phenylbutoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-4-(4-phenylbutoxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-4-(8-phenyloctyloxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-4-(8-phenyloctyloxy)benzoyl!amino-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-nitro-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,6-nitro-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran,8-nitro-6-chloro-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran and8-nitro-6-bromo-2-(S-methyl)isothiocarbamoyl-4-oxo-4H-benzopyran; andaryl group-containing isothioamides such as (S-methyl)isothiobenzamide,2-chloro-(S-methyl)isothiobenzamide,3-chloro-(S-methyl)isothiobenzamide,4-chloro-(S-methyl)isothiobenzamide, 2-bromo-(S-methyl)isothiobenzamide,3-bromo-(S-methyl)isothiobenzamide, 4-bromo-(S-methyl)isothiobenzamide,2-fluoro-(S-methyl)isothiobenzamide,3-fluoro-(S-methyl)isothiobenzamide,4-fluoro-(S-methyl)isothiobenzamide,2-methyl-(S-methyl)isothiobenzamide,3-methyl-(S-methyl)isothiobenzamide,4-methyl-(S-methyl)isothiobenzamide, 2-ethyl-(S-methyl)isothiobenzamide,3-ethyl-(S-methyl)isothiobenzamide, 4-ethyl-(S-methyl)isothiobenzamide,2-propyl-(S-methyl)isothiobenzamide,3-propyl-(S-methyl)isothiobenzamide,4-propyl-(S-methyl)isothiobenzamide, 2-butyl-(S-methyl)isothiobenzamide,3-butyl-(S-methyl)isothiobenzamide, 4-butyl-(S-methyl)isothiobenzamide,2-octyl-(S-methyl)isothiobenzamide, 3-octyl-(S-methyl)isothiobenzamide,4-octyl-(S-methyl)isothiobenzamide,2-pentadecyl-(S-methyl)isothiobenzamide,3-pentadecyl-(S-methyl)isothiobenzamide,4-pentadecyl-(S-methyl)isothiobenzamide,2-benzyl-(S-methyl)isothiobenzamnide,3-benzyl-(S-methyl)isothiobenzamnide,4-benzyl-(S-methyl)isothiobenzamide,2-phenethyl-(S-methyl)isothiobenzamide,3-phenethyl-(S-methyl)isothiobenzamide,4-phenethyl-(S-methyl)isothiobenzamide,2-(4-phenylbutyl)-(S-methyl)isothiobenzamide,3-(4-phenylbutyl)-(S-methyl)isothiobenzamide,4-(4-phenylbutyl)-(S-methyl)isothiobenzamide,2-(8-phenyloctyl)-(S-methyl)isothiobenzamide,3-(8-phenyloctyl)-(S-methyl)isothiobenzamide,4-(8-phenyloctyl)-(S-methyl)isothiobenzamide,2-(15-phenylpentadecyl)-(S-methyl)isothiobenzamide,3-(15-phenylpentadecyl)-(S-methyl)isothiobenzamide,4-(15-phenylpentadecyl)-(S-methyl)isothiobenzamide,2-methoxy-(S-methyl)isothiobenzamide,3-methoxy-(S-methyl)isothiobenzamide,4-methoxy-(S-methyl)isothiobenzamide,2-ethoxy-(S-methyl)isothiobenzamide,3-ethoxy-(S-methyl)isothiobenzamide,4-ethoxy-(S-methyl)isothiobenzamide,2-propoxy-(S-methyl)isothiobenzamide,3-propoxy-(S-methyl)isothiobenzamide,4-propoxy-(S-methyl)isothiobenzamide,2-butoxy-(S-methyl)isothiobenzamide,3-butoxy-(S-methyl)isothiobenzamide,4-butoxy-(S-methyl)isothiobenzamide,2-octyloxy-(S-methyl)isothiobenzamide,3-octyloxy-(S-methyl)isothiobenzamide,4-octyloxy-(S-methyl)isothiobenzamide,2-pentadecyloxy-(S-methyl)isothiobenzamide,3-pentadecyloxy-(S-methyl)isothiobenzamide,4-pentadecyloxy-(S-methyl)isothiobenzamide,2-benzyloxy-(S-methyl)isothiobenzamide,3-benzyloxy-(S-methyl)isothiobenzamide,4-benzyloxy-(S-methyl)isothiobenzamide,2-phenethyloxy-(S-methyl)isothiobenzamide,3-phenethyl-(S-methyl)isothiobenzamide,4-phenethyloxy-(S-methyl)isothiobenzamide,2-(4-phenylbutoxy)-(S-methyl)isothiobenzarnide,3-(4-phenylbutoxy)-(S-methyl)isothiobenzamide,4-(4-phenylbutoxy)-(S-methyl)isothiobenzamide,2-(8-phenyloctyloxy)-(S-methyl)isothiobenzamide,3-(8-phenyloctyloxy)-(S-methyl)isothiobenzamide,4-(8-phenyloctyloxy)-(S-methyl)isothiobenzamide,2-(15-phenylpentadecyloxy)-(S-methyl)isothiobenzamide,3-(15-phenylpentadecyloxy)-(S-methyl)isothiobenzamide,4-(15-phenylpentadecyloxy)-(S-methyl)isothiobenzamide,2-(1-phenyl)ethoxy-(S-methyl)isothiobenzamide,3-(1-phenyl)ethoxy-(S-methyl)isothiobenzamide,4-(1-phenyl)ethoxy-(S-methyl)isothiobenzamide,2-(S-methyl)isothiocarbamoyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-methyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-propyl- 1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-decyl- 1,1 '-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-hydroxymethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-hydroxy)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-hydroxy)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-hydroxy)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-hydroxy)octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-methoxymethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-methoxy)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-methoxy)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-methoxy)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-methoxy)octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-benzyloxymethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-benzyloxy)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-benzyloxy)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-benzyloxy)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-benzyloxy)octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-2-(4-methoxybenzyloxy)ethyl!-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-3-(4-methoxybenzyloxy)propyl!-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-4-(4-methoxybenzyloxy)-butyl!-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-8-(4-methoxybenzyloxy)octyl!-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-aminomethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-amino)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-amino)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-amino)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-amino)octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(N-mesylamino)methyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-mesylamino)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-mesylarmino)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-mesylamino)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-mesylamino)octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(benzyloxycarbonylamino)methyl- 1,I'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-benzyloxycarbonylamino)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-benzyloxycarbonylamino)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-benzyloxycarbonylamino)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-benzyloxycarbonylamino)octyl- 1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(tertiary-butoxycarbonylamino)methyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-tertiary-butoxycarbonylamino)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-tertiary-butoxycarbonylamino)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-tertiary-butoxycarbonylamino)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-tertiary-butoxycarbonylamino)octyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-chloromethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-bromomethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(2-bromo)ethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(3-bromo)propyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(4-bromo)butyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-(8-bromo)octyl-1,1 '-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-dichloromethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-trichloromethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-dibromomethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-tribromomethyl-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-methoxy-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-ethoxy-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-propoxy-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-butoxy-1,1'-biphenyl,2-(S-methyl)isothiocarbamoyl-4'-chloromethoxy-1,1'-biphenyl and2-(S-methyl)isothiocarbamoyl-4'-(2-chloro)ethoxy-1,1'-biphenyl.

The reaction of a hydrogen halide salt of isothioarnide (8) withhydrazine or a salt thereof can be effected as follows.

The reaction of a hydrogen halide salt of isothioamnide (8) withhydrazine or a salt thereof makes it possible to obtain a hydrogenhalide salt of amidrazone (6) which corresponds to amide (5) where R⁵ isan NH group and R⁶ is an NHNH₂ group as the production intermediate ofthe present invention.

The amount of hydrazine or a salt thereof, which is to be used, isusually from 1 to 20 moles, relative to isothioamide (8).

The above reaction is usually effected in the presence of an organicsolvent. As the solvent to be used, there can be mentioned those whichare inert to hydrazine or salts thereof, for example, hydrocarbons suchas benzene, toluene and hexane; halogenated hydrocarbons such asdichloromethane, dichloroethane and chlorobenzene; nitrated hydrocarbonssuch as nitrobenzene and nitromethane; ethers such as diethyl ether andtetrahydrofuran; amides such as dimethylformamide; and alcohols such asmethanol and ethanol. These can be used alone or as a mixture of two ormore kinds of solvents. The amount of solvent to be used, although itcan be appropriately determined, is usually from 1 to 100 times as muchas the weight of isothioamide (8).

There is no particular need to use any reaction additive such as anothercatalyst in the above reaction. When such a reaction additive is added,a base can be used, examples of which are pyridine compounds andalkylamines, such as pyridine, 2-methyl-5-ethylpyridine, triethylamineand tributylamine. The amount thereof is usually from 0.001 to 5 moles,preferably from 0.01 to 5 moles, and more preferably 0.1 to 5 moles,relative to the hydrogen halide salt of isothioamide (8).

The method and order for the addition of isothioamide (8), hydrazine ora salt thereof and a catalyst are not particularly limited, and usually,hydrazine or a salt thereof may be added to a mixture of isothioamide(9) and a solvent (and a base).

The reaction temperature is usually from -78° to +150° C., preferablyfrom -50° to +100° C. The completion of the reaction can be monitored byan analytical method such as liquid chromatography. Usually, thedisappearance of isothioamide (8) can be considered as the end point ofthe reaction.

After completion of the reaction, a hydrogen halide salt of amidrazone(6) can be isolated, for example, by an ordinary procedure such asextraction or filtration.

In general, amidrazone (6) is often unstable in free form, andtherefore, when isolated, amidrazone (6) is preferably converted intoits salt with hydrogen halide or the like.

The amidrazone (6) or a salt thereof can also be obtained. by reactingthioamide (7) with hydrazine or a salt thereof.

This reaction can be effected similarly to the above reaction of ahydrogen halide salt of isothioamide (8) with hydrazine or a saltthereof.

The reaction of a hydrogen halide salt of amidrazone (6) with nitrousacid compound (3) can be effected as follows.

The reaction of a hydrogen halide salt of amidrazone (6) with a nitrousacid compound makes it possible to produce tetrazole compound (1).

This reaction can be effected similarly to the above reaction ofamidrazone (6) with nitrous acid compound (3).

Thus, according to the present invention, it is possible to producetetrazole compounds in a simple and industrially favorable mannerwithout using any azide or any tin compound which is not desirable fromthe viewpoint of safety and waste matters treatment. The amide (5),which is the compound of the present invention, is useful as anintermediate for the production of tetrazole compounds.

The present invention will be further illustrated by the followingexamples, but the present invention is not limited to these examples.

Example 1

First, 2.0 g (4.56 mmol) of 8-4-(4-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran wassuspended in a mixture of 52 g of toluene, 0.23 g (2.28 mmol) oftriethylamine and 15 g of methanol, and 0.155 g of hydrogen sulfide gas(hydrogen sulfide, 47 mmol) was bubbled thereinto at room temperature.After stirring at room temperature for 3 hours, the completion of thereaction was checked by liquid chromatography, and the reaction mixturewas concentrated to give the corresponding thioamide. Product amount,2.15 g; yield, 99%; m.p., 203°-208° C.

Examples 2-5

The reaction in Example 1 was effected in the same manner as describedin Example 1, except that 2-cyano-4-oxo-4H-benzopyran,5-hydroxy-2-cyano-4-oxo-4H-benzopyran,6-chloro-2-cyano-4-oxo-4H-benzopyran or8-nitro-2-cyano-4-oxo-4H-benzopyran was used in place of 8-4-(4-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran, and thecorresponding thioamide was obtained.

The results are shown in Table 1.

                  TABLE 1    ______________________________________    Example    ______________________________________              Starting Material Name    2         2-Cyano-4-oxo-4H-benzopyran    3         5-Hydroxy-2-cyano-4-oxo-4H-benzopyran    4         6-Chloro-2-cyano-4-oxo-4H-benzopyran    5         8-Nitro-2-cyano-4-oxo-4H-benzopyran              Product    2         2-Thiocarbamoyl-4-oxo-4H-benzopyran              Yield, 88%; m.p., 225-231° C.    3         5-Hydroxy-2-thiocarbamoyl-4-oxo-4H-benzopyran              Yield, 98%    4         6-Chloro-2-thiocarbamoyl-4-oxo-4H-benzopyran              Yield, 95%; m.p., 284-289° C.    5         6-Nitro-2-thiocarbamoyl-4-oxo-4H-benzopyran              Yield, 97%; m.p., 223-228° C.    ______________________________________

Example 6

First, 2.00 g of 2-cyano-4'-methyl-1,1'-biphenyl was dissolved in amixture of 15 ml of methanol and 4.18 g of triethylamine, and hydrogensulfide gas was bubbled thereinto at room temperature to the point ofsaturation. After keeping at room temperature for 3 days, the solutionwas kept at 50° C. for 6 hours. The reaction mixture was concentratedunder reduced pressure, and the residue was extracted with ethyl acetatecontaining 1% hydrochloric acid. The organic layer was concentrated togive 2.18 g of 2-thiocarbamoyl-4'-methyl-1,1'-biphenyl. Yield, 92%;m.p., 111°-115° C.; m/z, 227

Examples 7-8

The procedures were repeated according to Example 6, except that thefollowing nitrites were used. The results are in Table 2.

                  TABLE 2    ______________________________________    Example    ______________________________________                   Starting Material Name    7              2-Chlorobenzonitrile    8              2-Cyano-1,1'-biphenyl                   Product    7              2-Chlorobenzthioamide                   Yield, 93%    8              2-Thiocarbamoyl-1,1'-biphenyl                   Yield, 95%    ______________________________________

Example 9

First, 2.15 g (4.55 mmol) of 8-4-(4-phenylbutoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran wassuspended in a mixture of 50 g of toluene and 10 g of methanol, and 0.15g (4.56 mmol) of anhydrous hydrazine was added thereto at 0° C. Afterstirring at 0°-5° C. for 8 hours, the reaction mixture was filtered togive 8-4-(4-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone.Product amount, 1.81 g; yield, 85%; m.p., 183°-186° C.

Example 10

First, 2.00 g (4.52 mmol) of 8-4-(4-phenylbutoxy)benzoyl!amino-2-cyano-4-oxo-4H-benzopyran and 0.69 g(6.77 mmol) of triethylamine were dissolved in 60 ml of dichloromethane,and 0.33 g (4.74 mmol) of hydrazine hydrochloride was added thereto,followed by keeping at 40° C. for 96 hours.

The reaction mixture was filtered to give 1.72 g of 8-4-(4-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone.Yield, 81%

Example 11

The reaction in Example 9 was effected in the same manner as describedin Example 9, except that 6-chloro-2-thiocarbamoyl-4-oxo-4H-benzopyranwas used in place of 8-4-(4-phenylbutoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, and2-(6-chloro-4-oxo-4H-benzopyran-2-yl)amidrazone was obtained in 85%yield.

Example 12

The procedure in Example 9 was repeated in the same manner as describedin Example 9, except that 2-chlorobenzthioamide was used in place of 8-4-(4-phenylbutoxy)benzoyl!amino-2-thiocarbamoyl-4-oxo-4H-benzopyran andhexane was added after the reaction at 60° C. for 48 hours, and2-chloro-benzamridrazone was obtained in 78% yield.

Example 13

First, 1.50 g of 2-thiocarbamoyl-4'-methyl-1,1'-biphenyl was dissolvedin 20 ml of acetone, and 1.10 g of methyl iodide was added thereto. At0° C. to room temperature, stirring was continued overnight. To thereaction mixture was added 45 ml of toluene, followed by filtration, and1.57 g of (4'-methyl-1,1'-biphen-2-yl)-S-methylisothioamide hydroiodidewas obtained. Yield, 87%; m.p., 165°-169° C. (decomp.)

Example 14

First, 1.00 g of 2-chlorobenzthioarmide was dissolved in 10 ml ofacetone, and 1.17 g of methyl iodide was added thereto. At 0° C. to roomtemperature, stirring was continued overnight. To the reaction mixturewas added 40 ml of ether, followed by filtration, and 1.40 g of2-chlorobenz-S-methylisothioamide hydroiodide was obtained. Yield, 85%;m.p., 127°-130° C.

Example 15

First, 1.30 g of (4'-methyl-1,1'-biphen-2-yl)-S-methylisothioamidehydroiodide was dissolved in 4 ml of methanol, and a solution of 0.12 gof anhydrous hydrazine dissolved in 1 ml of methanol was added for 30minutes. At 0° C. to room temperature, stirring was continued overnight,and about 50 ml of ether was added. The reaction mixture was filtered at0° C. to give 1.25 g of (4'-methyl-1,1'-biphen-2-yl)aridrazonehydroiodide. Yield, 96%; m.p., 140°-144° C. (decomp.)

Example 16

The procedure in Example 15 was repeated in the same manner as describedin Example 15, except that 2-chlorobenz-S-methylisothioamide hydroiodidewas used in place of (4'-methyl-1,1'-biphen-2-yl)-S-methylisothioamidehydrojodide, and (2-chlorobenz)amidrazone was obtained. Yield, 93%

Example 17

First, 2.08 g (4.11 mmol) of 8-4-(4-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone wasdissolved in 180 g of acetic acid, and 60 g of water and 0.42 g (6.17mmol) of sodium nitrite were added threreto, followed by stirring at0°-2° C. for 2 hours. After the completion of the reaction was checked,the reaction mixture was filtered to give 8-4-(4-phenylbutoxy)benzoyl!amino-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran.Product amount, 1.97 g; yield, 96%

Examples 18-20

The reaction in Example 17 was effected in the same manner as describedin Example 17, except that the startling materials shown in Table 3 wereused in place of 8-4-(4-phenylbutoxy)benzoyl!amino-4-oxo-4H-benzopyran-2-yl!amidrazone, andthe corresponding tetrazole compounds were obtained.

                  TABLE 3    ______________________________________    Example    ______________________________________             Starting Material Name    18       2-(6-Chloro-4-oxo-4H-benzopyran-2-yl)amidrazone    19       2-Chlorobenzamidrazone    20       (4'-Methyl-1,1'-biphenyl-2-yl)amidrazone hydroiodide             Product    18       6-Chloro-2-(tetrazol-5-yl)-4-oxo-4H-benzopyran             Yield, 93%    19       5-(2-Chlorophenyl)tetrazol             Yield, 80%    20       2-(Tetrazol-5-yl)-4'-methyl-1,1'-biphenyl             Yield, 86%    ______________________________________

Example 21

First, 71.2 mmol of 2-chlorobenzonitrile was dissolved in 50 ml ofmethanol, and 356 mmol of hydrazine and 35.6 mmol of 28% methylate wereadded thereto, followed by keeping at the reflux temperature for 5hours. The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in 50 ml of 50% hydrochloric acid, and 74.8 mmolof sodium nitrite was added thereto at 0° C. to cause reaction. Thereaction mixture was extracted with ethyl acetate to give5-(2-chlorophenyl)tetrazole. Yield, 70%.

Example 22

First, 26.9 mmol of 2-cyano-4'-methyl-1,1'-biphenyl was dissolved in 150ml of ethanol, and 270 mmol of hydrazine and 77.7 mmol of 28% methylatewere added thereto, followed by keeping at 50° C. for 48 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in 100 ml of ethanol, and 55 mmol of sodium nitrite and110 mmol of concentrated hydrochloric acid were added to the solution at0° C. After keeping at 0°-5° C. for 2 hours, the reaction mixture wasconcentrated to give 2-(tetrazol-5-yl)-4'-methyl-1,1'-biphenyl. Yield,46%

Example 23

First, 35.6 mmol of 2-chlorobenzonitrile was dissolved in 50 ml ofmethanol, and 35.6 mmol of triethylarnine and 105 mmol of hydrogensulfide were added thereto at room temperature, followed by adding 180mmol of anhydrous hydrazine and keeping at the reflux temperature for 48hours. The reaction mixture was evaporated under reduced pressure. Theresidue was dissolved in 50 ml of 5% hydrochloric acid, and 75 mmol ofsodium nitrite was added thereto at 0° C. to cause reaction. Aftercompletion of the reaction, the reaction mixture was extracted withethyl acetate to give 5-(2-chlorophenyl)tetrazole. Yield, 54%

Examples 24-27

The use of 2-bromobenzonitrile, 3-bromobenzonitrile, 2-nitrobenzonitrileor 3-nitrobenzonitrile in place of 2-chlorobenzonitrile in Example 21 or23 makes it possible to obtain the corresponding tetrazole compound:5-(2-bromophenyl)tetrazole, 5-(3-bromophenyl)tetrazole,5-(2-nitrophenyl)tetrazole or 5-(3-nitrophenyl)tetrazole.

Example 28

First, 26.9 mmol of 2-cyano-4'-methyl-1,1'-biphenyl was dissolved in 150ml of ethanol, and 53.9 mmol of triethylamine and 105 mmol of hydrogensulfide were added to the solution at room temperature, followed byadding 134.5 mmol of anhydrous hydrazine and keeping at the refluxtemperature for 48 hours. The reaction mixture was warmed. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in 100 ml of ethanol added thereto, and 108 mmol of sodiumnitrite and 100 ml of concentrated hydrochloric acid was added at 0° C.After keeping at 0°-5° C. for 2 hours, the reaction mixture wasextracted with ethyl acetate to give2-(tetrazol-5-yl)-4'-methyl-1,1'-biphenyl. Yield, 52%

Examples 29-31

The use of 2-cyano-1,1'-biphenyl, 2-cyano-4'-chloromethyl- 1,1'-biphenyl or 2-cyano-4'-methoxymethyl-1,1'-biphenyl in place of2-cyano-4'-methyl-1,1'-biphenyl in Example 28 makes it possible toobtain the corresponding compound: 2-(tetrazol-5-yl)-1,1'-biphenyl,2-(tetrazol-5-yl)-4'-chloromethyl-1,1'-biphenyl or2-(tetrazol-5-yl)-4'-methoxymethyl-1,1'-biphenyl.

Example 32

(1) Into a mixture of 4.13 g (30 mmol) of 2-chlorobenzonitrile, 30 g ofethanol, 1.10 g (15 mmol) of diethylamine and 1.92 g (60 mmol) ofanhydrous hydrazine was bubled 0.67 g (19.7 mmol) of hydrogen sulfidegas at room temperature, followed by stirring at 60° C. for 24 hours.The resulting reaction mixture was concentrated and dried to give 3.22 gof 2-chlorobenzamidrazone (63% yield). (2) First, 569 mg (3.35 mmol) of2-chlorobenzamidrazone produced according to (1) was dissolved in 15 gof N,N-dimethylformamide and 10.5 g (14.4 mmol) of 5% hydrochloric acid,followed by cooling to 5° C. Then, 2.96 g (4.29 mmol) of aqueous sodiumnitrite was added dropwise thereto, followed by stirring at 0°-5° C. for4 hours. The resulting reaction mixture was analyzed by liquidchromatography with an internal standard, and it was found that 583 mg(3.23 mmol, 96% yield) of 5-(2-chlorophenyl)tetrazole was contained.

The reaction mixture was concentrated to remove the solvent, and 40 g of4% aqueous sodium hydroxide and 30 ml of toluene were added to performan extraction and phase separation. The resulting aqueous layer wasfurther washed twice with 30 ml of toluene and adjusted to pH 1 or lowerby the addition of 36% hydrochloric acid The deposited solid wasfiltered and dried to give 508 mg (99.2% purity) of5-(2-chlorophenyl)tetrazole.

Example 33

Into a mixture of 4.13 g (30 mmol) of 2-chlorobenzonitrile, 30 g ofethanol, 1.10 g (15 mmol) of diethylamine and 1.92 g (60 mmol) ofanhydrous hydrazine was bubbled 0.62 g (18.2 mmol) of hydrogen sulfidegas at room temperature, followed by stirring at 60° C. for 9.5 hours.The resulting reaction mixture was concentrated, dried and dissolved in120 g of N,N-dimethylformamide and 54.7 g (150 mmol) of 10% hydrochloricacid added thereto, followed by cooling to 5° C. Then 20.7 g (60 mmol)of 20% sodium nitrite was added dropwise thereto, followed by stirringat 0°-5° C. for 3 hours. The resulting reaction mixture was filtered toremove undissolved matters. The filtrate was analyzed by liquidchromatography with an internal standard, and it was found that 3.76 g(20.8 mmol, 69% yield) of 5-(2-chlorophenyl)tetrazole was contained.

The filtrate was concentrated to remove the solvent, followed by thesame work up as described in Example 32, (2) to give 3.36 g (96.4%purity) of 5-(2-chlorophenyl)tetrazole.

Example 34

Into a mixture of 5.0 g (27.5 mmol) of 2-bromobenzonitrile, 30 g ofethanol, 1.10 g (15 mmol) of diethylamine and 1.76 g (55 mmol) ofanhydrous hydrazine was bubbled 0.58 g (17 mmol) of hydrogen sulfide gasat room temperature, followed by stirring at 60° C. for 22 hours. Theresulting reaction mixture was concentrated, dried and dissolved in 110g of N,N-dimethylformamide and 50.3 g (138 mmol) of 10% hydrochloricacid added thereto, followed by cooling to 5° C. Then, 19.0 g (55 mmol)of 20% sodium nitrite was added dropwise thereto, followed by stirringat 0°-5° C. for 2 hours. The resulting reaction mixture was filtered toremove undissolved matters. The filtrate was analyzed by liquidchromatography with an internal standard, and it was found that 4.88 g(21.7 mmol, 79% yield) of 5-(2-bromophenyl)tetrazole was contained.

The filtrate was concentrated to remove the solvent, followed by thesame work up as described in Example 32, (2) to give 4.75 g (93.1%purity) of 5-(2-bromophenyl)tetrazole.

We claim:
 1. An amide of formula (5):

    R.sup.1 C(=R.sup.5)R.sup.6                                 ( 5)

wherein R¹ represents either a 4-oxo-4H-benzopyranyl group of theformula: ##STR3## or a phenyl group substituted with X; R² is a hydroxygroup, a halogen atom, an R³ CONH group, a nitro group, a C₁ -C₅ alkylor C₁ -C₅ alkoxy group; R³ is a C₁ -C₂₀ alkyl group, a phenyl group, aphenyl-substituted (C₁ -C₂₀) alkyl group, a phenyl-substituted (C₁ -C₂₀)alkoxyphenyl group or a (C₁ -C₂₀) alkoxyphenyl group; n is 0 or 1; X isa phenyl group substituted with Y; Y is a C₁ -C₂₀ alkyl group, a C₁ -C₂₀alkyl group substituted with one or more hydroxy groups with optionallyone or more of the hydroxy groups having their hydrogen atom replacedwith a protecting group, a C₁ -C₂₀ alkyl group substituted with one ormore amino groups with optionally one or more of the amino groups havingtheir hydrogen atom replaced with a by a halogen atom, a C₁ -C₂₀ alkoxygroup, a C₁ -C₂₀ alkoxy group substituted with one or more hydroxygroups with optionally one or more of the hydroxy groups having theirhydrogen atom replaced with a protecting group, a C₁ -C₂₀ alkoxy groupsubstituted with one or more amino groups with optionally one or more ofthe amino groups having their hydrogen atom replaced with a protectinggroup, or a C₁ -C₂₀ alkoxy group with at least one hydrogen atom beingreplaced by a halogen atom; R⁵ is a sulfur atom; and R⁶ is an NH₂ group.2. An amide of formula (5):

    R.sup.1 C(=R.sup.5)R.sup.6                                 ( 5)

wherein R¹ represents either a 4-oxo-4H-benzopyranyl group of theformula: ##STR4## or a phenyl group substituted with X; R² is a hydroxygroup, a halogen atom, an R³ CONH group, a nitro group, a C₁ -C₅ alkylor C₁ -C₅ alkoxy group; R³ is a C₁ -C₂₀ alkyl group, a phenyl group, aphenyl-substituted (C₁ -C₂₀) alkyl group, a phenyl-substituted (C₁ -C₂₀)alkoxyphenyl group or a (C₁ -C₂₀) alkoxyphenyl group; n is 0 or 1; X isa halogen atom, a phenyl group optionally substituted with Y, a C₁ -C₂₀alkyl group, a phenyl-substituted (C₁ -C₂₀) alkyl group, aphenyl-substituted (C₁ -C₂₀) alkoxy group or a C₁ -C₂₀ alkoxy group; Yis a C₁ -C₂₀ alkyl group, a C₁ -C₂₀ alkyl group substituted with one ormore hydroxy groups with optionally one or more of the hydroxy groupshaving their hydrogen atom replaced with a protecting group, a C₁ -C₂₀alkyl group substituted with one or more amino groups with optionallyone or more of the amino groups having their hydrogen atom replaced witha protecting group, a C₁ -C₂₀ alkyl group with at least one hydrogenatom being replaced by a halogen atom, a C₁ -C₂₀ alkoxy group, a C₁ -C₂₀alkoxy group substituted with one or more hydroxy groups with optionallyone or more of the hydroxy groups having their hydrogen atom replacedwith a protecting group, a C₁ -C₂₀ alkoxy group substituted with one ormore amino groups with optionally one or more of the amino groups havingtheir hydrogen atom replaced with a protecting group or a C₁ -C₂₀ alkoxygroup with at least one hydrogen atom being replaced by a halogen atom;R⁵ is an NH group; and R⁶ is an SR⁴ group or an NHNH₂ group;wherein R⁴is a C₁ -C₂₀ alkyl group.
 3. An amide according to claim 2, wherein R⁵is an NH group and R⁶ is an SR₄ group.
 4. An amide according to claim 2,wherein R⁵ is an NH group and R⁶ is an NHNH₂ group.
 5. An amideaccording to claim 3, wherein R¹ is said phenyl group substituted withX, and X is said phenyl group optionally substituted with Y.
 6. An amideaccording to claim 4, wherein R¹ is said phenyl group substituted withX, and X is said phenyl group optionally substituted with Y.
 7. An amideaccording to claim 5, wherein X is a phenyl group or a (C₁ -C₂₀)alkylphenyl group.
 8. An amide according to claim 6, wherein X is aphenyl group or a (C₁ -C₂₀) alkylphenyl group.
 9. An amide according toclaim 3, wherein R¹ is said phenyl group substituted with X, and X is ahalogen atom.
 10. An amide according to claim 4, wherein R¹ is saidphenyl group substituted with X, and X is a halogen atom.
 11. The amideaccording to claim 1, wherein R¹ is a phenyl group substituted with X,and the group C(=R⁵)R⁶ is at position 2 on the benzene ring as depictedbelow: ##STR5## .